Comparative genomics of ape Plasmodium parasites reveals key evolutionary events leading to human malaria

African great apes are infected with at least six species of P. falciparum-like parasites, including the ancestor of P. falciparum. Comparative studies of these parasites and P. falciparum (collectively termed the Laverania subgenus) will provide insight into the evolutionary origins of P. falciparum and identify genetic features that influence host tropism. Here we show that ape Laverania parasites do not serve as a recurrent source of human malaria and use novel enrichment techniques to derive near full-length genomes of close and distant relatives of P. falciparum. Using a combination of single template amplification and deep sequencing, we observe no evidence of ape Laverania infections in forest dwelling humans in Cameroon. This result supports previous findings that ape Laverania parasites are host specific and have successfully colonized humans only once. To understand the determinants of host specificity and identify genetic characteristics unique to P. falciparum, we develop a novel method for selective enrichment of Plasmodium DNA from sub-microscopically infected whole blood samples. We use this technique to enrich for Laverania genomic DNA from chimpanzee blood samples and assemble near full length genomes for both close (P. reichenowi) and distant (P. gaboni) relatives of P. falciparum. Comparative analyses of these genomes to P. falciparum identify features that are conserved across the Laverania subgenus, including the expansion of the FIKK kinases and the presence of var-like multigene families in all Laverania species. Our analyses also identify genetic features that are unique to P. falciparum, such as a very low within-species diversity and a complex evolutionary history of the essential invasion genes RH5 and CyRPA. This dissertation lays the groundwork for future comparative analyses of the Laverania subgenus including population genomic analyses of ape parasites and comparisons of P. falciparum to its ancestor, P. praefalciparum